The present invention relates to a peptide having a vascular smooth muscle constrictor action. More particularly, the invention is directed to a new polypeptide or protein having a molecular weight of 2500.+-.300, which has vasoconstrictor action, and which is preferably obtained from mammalian or bird endothelial cells, and to methods of making and using that polypeptide, as well as to pharmaceutical compositions employing such polypeptide.
There have been reported endothelium-dependent vasoconstrictor reactions to various mechanical and chemical stimuli as well as endothelium-dependent vasodilative reactions. For example, it is known that vasoconstrictions can be induced by a mechanical load such as vascular stretch or increased vascular inner pressure, or can be chemically induced by such agents as thrombin, noradrenaline, vasopressin, bradykinin, conditions of anoxia, etc. It has also been reported that noradrenaline-induced vasoconstriction can be enhanced by use of neuropeptide Y. [K. Takemoto, Proc. Natl. Acad. Sci. U.S.A. 79, 5485 (1982); C. Minth et al., ibid. 81, 4577 (1984)]. However, no endothelium-derived humoral factor mediating these constrictor reactions has yet been identified. Endothelial cell-derived coronary vascular constrictor factors (each having molecular weights of 8,500 and 3,000) are described in Physiol. 248, C550 (1985) A. K. Hickey et al., Am. J. and J. Cell. Physiol. 132, 263 (1987) (R. F. O'Brien et al.). However, their structures are unknown. An endothelial cell-derived peptide-like substance is also described in J. Pharmac. Exp. Ther. 236, 339 (1985) (M. N. Gillespie et al.). However, the structure of that substance is also unknown.
Certain peptides having a vasoconstrictor activity are known, such as vasopressin, bradykinin and the like, the amino acid sequences of which have been determined. It has not been reported, however, that such peptides were obtained from mammalian or bird vascular endothelial cells. Further, there is a report that angiotensin having a vasoconstrictor activity is obtained from the endothelial cells of bovine aortas [I. Kifor and V. J. Dzav, Circ. Res. 60, 422 (1987)]. However, angiotensin is a peptide having a molecular weight of about 1,000.